POS0105 IMMUNOLOGICAL AND TISSUE DERIVED BIOMARKERS OF EARLY RESPONSE IN MODERATE-TO-SEVERE RHEUMATOID ARTHRITIS TREATED WITH JAK-INHIBITORS
Authors: S. Perniola, B. Tolusso, C. DI Mario, M. Gessi, D. Bruno, V. Varriano, A. Paglionico, L. Petricca, M. R. Gigante, M. A. D’agostino, S. Alivernini, E. Gremese
Journal: Annals of the Rheumatic Diseases (2022)

Background Among Janus kinase inhibitors (JAKi) approved for Rheumatoid Arthritis (RA) treatment, tofacitinib and baricitinib are considered as pan-JAKi (pJAKi) while upadacitinib and filgotinib as selective anti-JAK1 (sJAKi) drugs. To date, despite ≈30% of RA patients exposed to JAKi achieve DAS28-CRP remission at 12 weeks, there is still lack of predictive biomarkers of response in RA treated with distinct JAKi. Objectives To determine whether pre-treatment immunological and synovial tissue features can predict clinical improvement in moderate-to-severe RA treated with JAKi. Methods Among 174 RA patients treated with JAKi, 84 underwent peripheral blood (PB) drawing and US-guided synovial tissue (ST) biopsy. Demographic, clinical and immunological features were collected for each patient at baseline and after 12 weeks. The distribution of PB-derived B lymphocytes subsets was assessed by flow cytometry, using CD27/IgD classification. Synovitis degree assessment was determined using Krenn score (KSS) by trained pathologist, blinded to clinical characteristics. Results Among enrolled RA patients, 82.7% was treated with pJAKi and 17.3% with sJAKi. Moreover, 35.6% of RA patients was b/ts-DMARDs naïve, 18.4% b/ts-DMARDs non-responder and 46.0% was difficult-to-treat (D2T) RA. In the whole cohort, 49.2% and 50.8% of RA patients achieved DAS28-CRP and CDAI low disease activity (LDA), respectively, after 12 weeks of JAKi treatment. Moreover, 37.7% and 5.9% of RA patients achieved DAS28-CRP and CDAI remission (REM), respectively, after 12 weeks of JAKi treatment regardless to JAKi category. Considering the immunological profile, RA patients achieving CDAI LDA were more likely rheumatoid factor (60.0%) and ACPA positive (60.5%) compared to RA patients not achieving this outcome (RF: 40.0%, p= 0.03 and ACPA: 39.5%, p= 0.02). Considering PB-derived B cell phenotype, b/ts-DMARDs naïve RA achieving DAS28-CRP LDA at 12 week had pre-treatment lower unswitched memory B (IgD pos CD27 pos ) cell rate (6.91±7.70%) compared to b/ts-DMARDs naïve RA not achieving the same outcome (13.21±5.68%, p= 0.009). ROC analysis identified a cut-off value of 6.89% for IgD pos CD27 pos cells discriminating b/ts-DMARDs naïve RA achieving DAS28-CRP LDA at 12 week [AUC: 0.174±0.086; p= 0.008; OR(95%CIs): 18.20 (1.761-188.069)]. Furthermore, b/ts-DMARDs naïve RA achieving DAS28-CRP REM at 12-week follow up visit, had PB enrichment of naïve B cells (IgD pos CD27 neg : 68.08±17.38%) and lower percentage of unswitched memory B lymphocytes (5.10±4.29%) compared to RA not achieving the same outcome (IgD pos CD27 neg : 54.68±16.16%, p= 0.05; IgD pos CD27 pos : 13.96±8.34%, p= 0.001) [IgD pos CD27 neg cut-off: 62.6%, AUC:0.727±0.101, p=0.05; OR(95%CIs): 7.33(1.272-42.294); IgD pos CD27 pos cut-off: 6.89%, AUC: 0.139±0.073, p= 0.002; OR(95%CIs): 12.37 (1.828-83.767)]. Interestingly, considering the D2T RA subgroup, patients achieving DAS28-CRP LDA at 12 week follow up had lower rates of PB-derived IgD neg CD27 neg B cells (3.83±0.96%) compared to RA not achieving the same outcome (7.25±2.83%, p= 0.04; cut-off: 5.46%, AUC: 0.083±0.095, p=0.041). Considering the pre-treatment synovitis degree, b/ts-DMARDs naïve RA achieving CDAI LDA status had significantly higher KSS at baseline (3.8±2.2) compared to RA not achieving the same outcome [1.7±1.4, p= 0.02; KSS cut-off: 3.00, AUC: 0.795±0.097; p=0.018; OR(95%CIs): 14.0 (1.39-141.49)]. Finally, no significant associations were observed between PB-derived B cell subpopulations rate and synovitis degree both in the whole RA cohort as well as stratifying patients for disease phase. Conclusion Pre-treatment immunological profile, peripheral blood-derived B cell phenotype and synovitis degree are associated with the early achievement of at least DAS28-CRP/CDAI LDA in RA patients receiving JAKi despite their selectivity. References [1]Gremese E et. J Leukoc Biol . 2019 [2]Alivernini S et al. Pharmacol Res. 2019 [3]Alivernini S et al. Arthritis Rheumatol. 2021 Disclosure of Interests None declared